`571-272-7822
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` Paper 86
` Entered: August 24, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MYLAN PHARMACEUTICALS INC. and AMNEAL
`PHARMACEUTICALS LLC,
`Petitioners,
`
`v.
`
`YEDA RESEARCH & DEVELOPMENT CO. LTD.,
`Patent Owner.
`
`____________
`
`Case IPR2015-00644
`Patent 8,399,413 B21
`____________
`
`
`
`Before SHERIDAN K. SNEDDEN, ZHENYU YANG, and
`TINA E. HULSE, Administrative Patent Judges.
`
`HULSE, Administrative Patent Judge.
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`
` 1
`
` Case IPR2015-01980 has been joined with Case IPR2015-00644.
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`IPR2015-00644
`Patent 8,399,413 B2
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`INTRODUCTION
`
`Mylan Pharmaceuticals Inc. (“Petitioner”) filed a corrected
`Petition requesting an inter partes review of claims 1–20 of U.S.
`Patent No. 8,399,413 B2 (Ex. 1001, “the ’413 patent”). Paper 8
`(“Pet.”). Yeda Research & Development Co. Ltd. (“Patent Owner”)
`filed a Preliminary Response to the Petition. Paper 12 (“Prelim.
`Resp.”). On August 25, 2015, we instituted an inter partes review of
`claims 1–20 on two grounds of obviousness. Paper 14 (“Dec. Inst.”),
`16. Patent Owner filed a Response to the Petition. Paper 27 (“PO
`Resp.”). Petitioner filed a Reply to Patent Owner’s Response. Paper
`59 (“Pet. Reply”).
`On September 25, 2015, Amneal Pharmaceuticals LLC
`(“Amneal”) also filed a Petition requesting an inter partes review of
`claims 1–20 of the ’413 patent in case IPR2015-01980 (“the -1980
`case”). IPR2015-01980, Paper 1. Amneal filed a motion to join
`the -1980 case with this case. Id., Paper 3. On December 28, 2015,
`we granted Amneal’s Petition and its motion for joinder. Id., Paper 9.
`Accordingly, we terminated the -1980 case and joined the -1980 case
`with this case.
`Both parties filed motions to exclude certain exhibits and
`testimony. Paper 68 (Patent Owner); Paper 70 (Petitioner). Both
`parties filed oppositions. Paper 76 (Petitioner Opposition); Paper 73
`(Patent Owner Opposition). And both parties filed replies in support
`of their motions to exclude. Paper 80 (Patent Owner Reply); Paper 81
`(Petitioner Reply).
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`Patent Owner filed observations on the cross-examination of
`Petitioners’ declarants, Ari Green, M.D. and Joel W. Hay, Ph.D.
`Paper 72. Petitioner filed a response to Patent Owner’s observations.
`Paper 78.
`An oral hearing for this proceeding was held on May 11, 2016,
`a transcript of which has been entered in the record. Paper 85 (“Tr.”)
`We have jurisdiction under 35 U.S.C. § 6(c). This Final
`Written Decision is issued pursuant to 35 U.S.C. § 318(a) and
`37 C.F.R. § 42.73.
`For the reasons that follow, we determine that Petitioner has
`shown by a preponderance of the evidence that claims 1–20 of the
`’413 patent are unpatentable.
`Related Proceedings
`A.
`Petitioner states that it is a defendant in several litigations
`involving the ’413 patent. Pet. 2. Petitioner also identifies numerous
`other cases against other defendants involving the ’413 patent. Id.
`We also instituted inter partes review of related patents in
`IPR2015-00643 (US 8,232,250 B2) and IPR2015-00830 (US
`8,969,302 B2).
`
`The ’413 Patent (Ex. 1001)
`B.
`Multiple sclerosis (“MS”) is a chronic, autoimmune disease of
`the central nervous system. Ex. 1001, 1:16–18. There are five main
`forms of MS, including Relapsing-Remitting Multiple Sclerosis
`(“RRMS”). Id. at 1:29. Patients suffering from RRMS experience
`sporadic exacerbations or relapses, as well as periods of remission.
`Id. at 1:30–31.
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`Glatiramer acetate (“GA” or “copolymer-1”) is a mixture of
`polypeptides that do not all have the same amino acid sequence, and is
`marketed as Copaxone®. Id. at 1:63–65. Administering 20 mg per
`day of Copaxone is an FDA-approved therapy for patients with
`RRMS. Id. at 2:13–16. The ’413 patent discloses “an effective low
`frequency dosage regimen of GA administration to patients suffering
`from a relapsing form of [MS], including patients who have
`experienced a first clinical episode and have MRI features consistent
`with [MS].” Id. at 2:43–47. The disclosed method comprises
`administering to a patient suffering from RRMS three subcutaneous
`injections of a therapeutically effective dose of GA over a period of
`seven days with at least one day between every subcutaneous injection
`to alleviate a symptom of the patient. Id. at 2:51–60.
`Illustrative Claim
`C.
`Petitioner challenges claims 1–20 of the ’413 patent.
`Claim 1 is illustrative and is reproduced below:
`1. A method of reducing the frequency of relapses in a
`human patient suffering from relapsing-remitting multiple
`sclerosis or a patient who has experienced a first clinical
`episode and has MRI features consistent with multiple
`sclerosis comprising administering to the human patient a
`three
`therapeutically effective dosage
`regimen of
`subcutaneous injections of 1 ml of a pharmaceutical
`composition comprising 40 mg of glatiramer acetate over
`a period of seven days with at least one day between every
`subcutaneous injection, the regimen being sufficient to
`reduce the frequency of relapses in the patient.
`
`Ex. 1001, 16:26–36 (emphasis on limitation at issue added).
`
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`Claims 19 and 20 are the remaining independent claims, and both
`claims recite the same dosing limitation of “three subcutaneous
`injections of 1 ml of a pharmaceutical composition comprising 40 mg
`of glatiramer acetate over a period of seven days with at least one day
`between every subcutaneous injection.” Id. at 18:4–7 (claim 19),
`18:19–22 (claim 20).
`D. Grounds of Unpatentability Instituted for Trial
`We instituted trial based on the following grounds of
`unpatentability:
`Claim(s)
`1–20
`
`Basis
`§ 103
`
`1–20
`
`
`
`§ 103
`
`References
`Pinchasi2 and the 1996
`SBOA3
`Pinchasi and Flechter4
`
`ANALYSIS
`
`The Level of Ordinary Skill in the Art
`A.
`The parties dispute the proper definition of a person of ordinary
`skill in the art. Petitioner contends that a person of ordinary skill in
`the art would have had (1) several years of experience in the
`pharmaceutical industry or in practicing medicine; (2) experience with
`
`
`
` 2
`
` Irit Pinchasi, WO 2007/081975 A2, published July 19, 2007
`(Ex. 1005).
`3 Summary Basis of Approval (“SBOA”) for the New Drug
`Application for 20 mg daily Copaxone ® (NDA #20-622) (Ex. 1007).
`4 S. Flechter et al., Copolymer 1 (Glatiramer Acetate) in Relapsing
`Forms of Multiple Sclerosis: Open Multicenter Study of Alternate-Day
`Administration, 25 CLINICAL NEUROPHARM. 11–15 (2002) (Ex. 1008).
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`the administration or formulation of therapeutic agents, dosing
`schedules and frequencies, and drug developmental study and design;
`and (3) a Ph.D. in pharmacology or be a physician with experience in
`clinical pharmacology. Pet. 12. In its Preliminary Response, Patent
`Owner disagreed with Petitioner’s definition because it does not
`include experience with MS or GA, which, according to Patent
`Owner, are both requirements for a person of ordinary skill in the art.
`Prelim. Resp. 34–35.
`In our Decision to Institute, we agreed with Patent Owner that a
`person of ordinary skill in the art should have experience with MS and
`GA. Dec. Inst. 5. We noted that one of Petitioner’s declarants, Dr.
`Ari Green, states that a person of ordinary skill in the art would have
`“direct experience administering therapeutic agents for the treatment
`of MS, as well as familiarity with the dosing schedules and
`frequencies of the different therapeutic agents available for MS
`treatment.” Id. (citing Ex. 1004 ¶ 27).
`During trial, neither Petitioner nor Patent Owner party
`contested our definition of the level of a person of ordinary skill in the
`art. Upon considering the full record, we see no reason to deviate
`from our prior determination, and we adopt Petitioner’s definition of a
`person of ordinary skill in the art, with the addition that that person
`would also have experience treating MS with GA.
`Claim Construction
`B.
`In an inter partes review, the Board interprets claim terms in an
`unexpired patent according to the broadest reasonable construction in
`light of the specification of the patent in which they appear. 37 C.F.R.
`
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`§ 100(b); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46
`(2016). Under that standard, and absent any special definitions, we
`give claim terms their ordinary and customary meaning, as would be
`understood by one of ordinary skill in the art at the time of the
`invention. See In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed.
`Cir. 2007). Any special definitions for claim terms must be set forth
`with reasonable clarity, deliberateness, and precision. See In re
`Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
`In our Decision to Institute, we determined that the broadest
`reasonable interpretation of the claims does not encompass a dosage
`regimen that alternates days over a period of seven days (i.e., one that
`administers the drug three times in one week and four times the next).
`Dec. Inst. 5–8. Neither Petitioner nor Patent Owner challenged this
`construction during trial. See generally Pet. Reply; see PO Resp. 6–7
`(stating the Board correctly construed the claims). Accordingly,
`because nothing in the full record developed during trial persuades us
`to deviate from our prior construction, we adopt the construction for
`purposes of this Decision.5
`
`
`
` 5
`
` We note that Patent Owner states that the Board correctly found that
`claim 3 “merely contains a typographical error and properly depends
`from claim 2.” PO Resp. 6–7. It appears, however, that Patent Owner
`was referring to case IPR2015-00643 and claim 3 of the ’250 patent,
`not the ’413 patent.
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`Principles of Law
`C.
`To prevail in this inter partes review of the challenged claims,
`Petitioner must prove unpatentability by a preponderance of the
`evidence. 35 U.S.C. § 316(e); 37 C.F.R. § 42.1(d).
`A patent claim is unpatentable under 35 U.S.C. § 103(a) if the
`differences between the claimed subject matter and the prior art are
`such that the subject matter, as a whole, would have been obvious at
`the time the invention was made to a person having ordinary skill in
`the art to which the subject matter pertains. KSR Int’l Co. v. Teleflex
`Inc., 550 U.S. 398, 406 (2007). The question of obviousness is
`resolved on the basis of underlying factual determinations, including:
`(1) the scope and content of the prior art; (2) any differences between
`the claimed subject matter and the prior art; (3) the level of skill in the
`art; and (4) objective evidence of nonobviousness. Graham v. John
`Deere Co., 383 U.S. 1, 17–18 (1966).
`“[A] patent composed of several elements is not proved obvious
`merely by demonstrating that each of its elements was, independently,
`known in the prior art.” KSR, 550 U.S. at 418. “[I]t can be important
`to identify a reason that would have prompted a person of ordinary
`skill in the relevant field to combine elements in the way the claimed
`new invention does.” Id. Moreover, a person of ordinary skill in the
`art must have had a reasonable expectation of success of doing so.
`PAR Pharm., Inc. v. TWi Pharms., Inc., 773 F.3d 1186, 1193 (Fed.
`Cir. 2014).
`We analyze the instituted grounds of unpatentability in
`accordance with the above-stated principles.
`
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`D. Obviousness over Pinchasi and the 1996 SBOA
`
`Petitioner argues that claims 1–20 are unpatentable as obvious
`over Pinchasi and the 1996 SBOA. Pet. 51–55. Based on the full trial
`record, we determine that Petitioner has established by a
`preponderance of the evidence that claims 1–20 are unpatentable over
`Pinchasi and the 1996 SBOA.
`Pinchasi (Ex. 1005)
`1.
`Pinchasi is a published PCT application that relates to a method
`of alleviating a symptom of a patient suffering from a relapsing form
`of MS. Ex. 1005, 9.6 The method comprises periodically
`administering by subcutaneous injection a 40 mg dose of GA. Id.
`Pinchasi discloses that the GA can be administered daily or every
`other day. Id. Pinchasi also discloses that the alleviated symptom can
`be the frequency of relapses. Id.
`The 1996 SBOA (Ex. 1007)
`2.
`The 1996 SBOA is a compilation of documents relating to the
`Summary Basis of Approval for the New Drug Application (“NDA”)
`for 20 mg Copaxone®. The compilation includes a review and
`evaluation of clinical data submitted by the sponsor of the NDA, Teva
`Pharmaceuticals, USA (“Teva”). Ex. 1007, 24–124. Certain
`reviewers raised the question of whether daily injections of the drug
`were necessary, stating “I would recommend that the Sponsor
`
`
`
` 6
`
` Unless stated otherwise, we cite to the unique page numbers
`provided by the parties in the lower right hand corner of the exhibits,
`pursuant to 37 C.F.R. 42.63(d)(2).
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`evaluate the necessity of daily [subcutaneous] injections as opposed to
`more infrequent intermittent administration of the drug.” Id. at 252.
`The 1996 SBOA also includes a review of the pharmacology and
`toxicology studies submitted by Teva. Id. at 125–292. The NDA
`was approved on December 20, 1996. Id. at 4.
`Analysis
`3.
`We have reviewed the arguments and evidence presented by
`both parties, and we are persuaded that Petitioner has shown by a
`preponderance of the evidence that the challenged claims are
`unpatentable as obvious over Pinchasi and the 1996 SBOA.
`a. Whether the 1996 SBOA Is a Printed Publication
`As an initial matter, we note that Patent Owner argued in its
`Preliminary Response that Petitioner failed to establish that the 1996
`SBOA is a printed publication under 35 U.S.C. § 102(b). Prelim.
`Resp. 48–50. Patent Owner does not, however, challenge the
`reference in its Patent Owner Response.
`Nevertheless, on this record, we determine that Petitioner has
`shown sufficiently that the 1996 SBOA constitutes prior art to the
`’413 patent. As support, Petitioner offers a declaration from Marlene
`S. Bobka, the president of FOI Services, Inc., which provided the
`1996 SBOA to Petitioner. Ex. 1007, 1. Ms. Bobka states that FOI
`Services specializes in U.S. Food & Drug Administration (“FDA”)
`information and “maintains a private library of over 150,000 FDA
`documents obtained under the Freedom of Information Act.” Id. Ms.
`Bobka further states that FOI Services sells the documents and
`provided the 1996 SBOA to Petitioner on July 17, 2007. Id. Because
`
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`the uncontroverted evidence shows Petitioner was able to obtain the
`1996 SBOA from FOI Services on July 17, 2007, we determine that
`the 1996 SBOA was publicly available at least as of that date, which
`is before the earliest possible critical date of the ’413 patent (i.e.,
`August 20, 2008). See Ex. 1001, [60]; see also Voter Verified, Inc. v.
`Premier Election Solutions, 698 F.3d 1374, 1380 (Fed. Cir. 2012)
`(“[T]he key inquiry is whether the reference was made ‘sufficiently
`accessible to the public interested in the art’ before the critical date.’”)
`(quoting In re Cronyn, 890 F.2d 1158, 1160 (Fed. Cir. 1989)).
`Independent Claims 1, 19, and 20
`b.
`We next consider whether claims 1–20 are unpatentable as
`obvious over Pinchasi and the 1996 SBOA. Regarding independent
`claims 1, 19, and 20, we are persuaded by Petitioner and the testimony
`of its declarant, Dr. Ari Green, that Pinchasi discloses each limitation
`of the claims, except for the dosing regimen of three doses per seven
`day period. See Ex. 1004 ¶¶ 82–84. Specifically, Petitioner argues
`that Pinchasi teaches the preamble of the claims by disclosing that the
`invention provides a method of alleviating a symptom of a patient
`suffering from a relapsing form of MS, where the symptom is the
`“frequency of relapses.” Pet. 21 (citing Ex. 1005, 8:2–4, 14–15).7
`Regarding the dosage amount of 1 mL of a pharmaceutical
`composition comprising 40 mg of GA, Petitioner asserts that Pinchasi
`teaches administering a subcutaneous injection of a pharmaceutical
`
`
`
` 7
`
` We note that the Petition cites the page numbers of Pinchasi rather
`than the page number provided pursuant to 37 C.F.R. § 42.63(d)(2)
`
`11
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`composition comprising 40 mg of GA and 40 mg of Mannitol USP in
`1 mL sterilized water. Id. at 22–23 (citing Ex. 1005, 5:2–8, 13:21–24,
`Example 1).
`Patent Owner does not contest that Pinchasi teaches these claim
`limitations. Accordingly, based on the full record developed at trial,
`we determine for the reasons stated in the Petition that Pinchasi
`teaches each limitation of claims 1, 19, and 20, with the exception of
`the dosing frequency of three times per week. See id. at 21–23.
`Petitioner argues that the dosing frequency would have been
`obvious because an ordinary artisan would have considered six doses
`over two seven-day periods to be therapeutically equivalent to and
`have substantially the same pharmacological effect as seven doses
`over the same period. Id. at 46 (citing Ex. 1004 ¶¶ 89–94, 104–106;
`Ex. 1003 ¶¶ 122–25). Petitioner further argues that an ordinary
`artisan would have been motivated to modify the dosing regimen of
`Pinchasi to exactly three injections per seven-day period to reduce the
`frequency of injections, which would reduce the frequency of side
`effects. Id. at 46–47 (citing Ex. 1004 ¶¶ 103, 104, 109; Ex. 1003
`¶¶ 116, 166, 167, 170). Three injections per week would also allow
`for a more convenient dosing schedule, which would improve patient
`compliance with the dosing regimen. Id. at 47 (citing Ex. 1004 ¶ 105;
`Ex. 1003 ¶¶ 107–10). Petitioner also contends that the 1996 SBOA
`teaches that the half-life for Copaxone® is approximately 80 hours in
`a Cynomolgus monkey, and that pharmacokinetic data from such a
`monkey was a reliable model for predicting human pharmacokinetic
`parameters and creating dosing schedules. Pet. 52 (citing Ex. 1007A,
`
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`66; Ex. 1003 ¶¶ 127, 133, 136–38). Accordingly, Petitioner argues
`that a person of ordinary skill in the art would have understood that
`injection frequencies could be reduced as far as approximately once
`every 80 hours while maintaining the same safety and tolerability
`profiles. Id. at 53 (citing Ex. 1003 ¶¶ 139–41).
`In response, Patent Owner urges that a person of ordinary skill
`in the art would not have found the claimed dosing regimen obvious.
`Patent Owner argues that an ordinary artisan would not have used 40
`mg of GA on any dosing schedule, and would not have used a three
`times per week regimen. PO Resp. 17–32. Patent Owner also argues
`that there was no motivation to combine Pinchasi with the 1996
`SBOA. Id. at 32–35. Finally, Patent Owner argues that an ordinary
`artisan would not have had a reasonable expectation of success that a
`40 mg dose of GA three times a week would be therapeutically
`effective. Id. at 36–50.
`Upon reviewing the entire trial record, we determine that
`Pinchasi teaches each limitation of claim 1, with the exception of the
`claimed dosing limitation. Moreover, for the reasons explained in the
`Petition and by Petitioner’s experts, Drs. Peroutka and Green, we
`determine that a person of ordinary skill in the art would have had a
`reason to modify Pinchasi to administer 40 mg of GA three times a
`week. In particular, we credit the testimony of Dr. Green, who notes
`that Pinchasi demonstrates increased efficacy with 40 mg GA when
`compared to 20 mg GA with no significant difference in side effects.
`Ex. 1004 ¶¶ 98–99. Indeed, Pinchasi concludes:
`
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`The increased efficacy observed with 40 mg/day GA in
`reducing MRI-measured disease activity and relapse rate
`indicates that it is well tolerated and can improve the
`treatment of RRMS patients. The improvement in
`efficacy, however, is not accompanied by a corresponding
`increase of adverse reactions which would be expected
`upon a doubling of the administered dose.
`
`Also observed was the accelerated rate at which the 40
`mg/day dose became effective as compared to the 20
`mg/day dose. This was unexpected. Specifically, the 40
`mg/day dose showed efficacy, as measured by MRI, by the
`third month, whereas the 20 mg/day dose did not show
`efficacy until the sixth month.
`
`Ex. 1005, 20:8–21:6. We are therefore persuaded by Dr. Green’s
`testimony that Pinchasi would have strongly suggested to an ordinary
`artisan to use 40 mg GA for RMSS patients. See Ex. 1004 ¶¶ 99.
`Patent Owner argues that a person of ordinary skill in the art
`would not have used 40 mg of GA because a later phase III clinical
`trial (the “FORTE trial”) demonstrated that 40 mg of GA was not
`more effective than 20 mg of GA, and 40 mg of GA was associated
`with more frequent adverse events. PO Resp. 17–20. Upon
`considering the evidence as a whole, we are not persuaded. That the
`FORTE trial found that “the 40 mg dose did not demonstrate
`increased efficacy in reducing the relapse rate” does not amount to
`teaching away from the 40 mg dose. Ex. 2001, 1 (emphasis added).
`This is particularly true where the FORTE trial then states that “the
`higher [40 mg] dose maintained the favorable safety and tolerability
`profile of COPAXONE® 20mg.” Id. Thus, because nothing in
`FORTE criticizes, discredits, or discourages the use of 40 mg of GA,
`
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`we determine that FORTE does not teach away from the use of 40 mg
`of GA. See In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004)
`(finding “[t]he prior art’s mere disclosure of more than one alternative
`does not constitute a teaching away from any of these alternatives
`because such disclosure does not criticize, discredit, or otherwise
`discourage the solution claimed”).
`We also determine that an ordinary artisan would have had a
`reason to modify Pinchasi’s dosing regimen of 40 mg of GA every
`other day to 40 mg of GA three times a week. We are persuaded by
`Dr. Green’s testimony that an ordinary artisan would have been
`motivated to adopt a three times per week dosing regimen to increase
`patient compliance. For example, Dr. Green testifies that it was a
`well-known principle that decreasing the frequency of injections
`would have a positive impact on patients to stay on course with
`treatment. Ex. 1004 ¶ 100. The desirability of less frequent injections
`is supported by the 1996 SBOA, which “recommend[ed] that [Teva]
`evaluate the necessity of daily s.c. injections as opposed to more
`infrequent intermittent administration of the drug.” Ex. 1004 ¶¶ 101–
`02; Ex. 1085 ¶ 17 (quoting Ex. 1007, 252).
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`As support for the well-known desirability of less frequent
`injections of GA, Dr. Green also cites Khan 20088 and Caon 20099,
`which both disclose a pilot trial comparing the effect of 20 mg of GA
`daily versus every other day.10 Ex. 1085 ¶ 18. The study suggests
`that 20 mg of GA daily or every other day may be equally effective in
`treating RRMS. Ex. 1010; Ex. 1011. Moreover, after two years, “all
`patients in the [daily] group opted to switch to [every other day].”
`Ex. 1010; Ex. 1011.
`Dr. Green also cites Khan 2009,11 which discloses another pilot
`study comparing 20 mg of GA daily or twice a week.12 Ex. 1085 ¶
`32. Although Khan 2009 was published three weeks after the priority
`date of the ’413 patent, Khan 2009 reports results of a two-year study.
`
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`
` 8
`
` Khan et al., Randomized, Prospective, Rater-Blinded, Four-Year,
`Pilot Study to Compare the Effect of Daily Versus Every-Other-Day
`Glatiramer Acetate 20 mg Subcutaneous Injections in Relapsing-
`Remitting Multiple Sclerosis, 14 MULTIPLE SCLEROSIS S296 (2008)
`(Ex. 1010) (“Khan 2008”).
`9 Caon et al., Randomized, Prospective, Rater-Blinded, Four-Year,
`Pilot Study to Compare the Effect of Daily Versus Every-Other-Day
`Glatiramer Acetate 20 mg Subcutaneous Injections in RRMS, 72
`NEUROLOGY A317 (Mar. 17, 2009) (Ex. 1011) (“Caon 2009”).
`10 The parties’ declarants agree that Khan 2008 and Caon 2009
`describe the same pilot study. Ex. 1085 ¶ 18; Ex. 2135, 73 n.2.
`11 Khan et al., Glatiramer Acetate 20 mg Subcutaneous Twice-Weekly
`Versus Daily Injections: Results of a Pilot, Prospective, Randomized,
`and Rater-Blinded Clinical and MRI 2-Year Study in Relapsing
`Remitting Multiple Sclerosis, 15 MULTIPLE SCLEROSIS S249 (2009)
`(Ex. 1089) (“Khan 2009”).
`12 We understand Patent Owner has moved to exclude Khan 2009.
`We deny Patent Owner’s motion for the reasons stated in more detail
`below.
`
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`Ex. 1089, 2. Upon finding similar results between the two dosing
`regimens after two years, Khan 2009 states: “This study provides
`further evidence that GA administered less frequently than daily may
`be as efficacious and better tolerated than GA administered daily.
`This may have a significant impact on improving compliance and
`tolerability while maintaining the desired immunomodulating effect of
`GA.” Id. We therefore agree with Dr. Green that Khan 2009 suggests
`that those skilled in the art at the time of the invention were motivated
`to investigate dosing regimens of GA with fewer injections to improve
`patient compliance.
`Moreover, Pinchasi discloses administration of the 40 mg dose
`every other day. Ex. 1005, 9:1−11. Thus, the difference between the
`challenged claims and the prior art is a dosing schedule that is
`decreased by one day every two weeks—i.e., the difference between
`every other day disclosed in the prior art and the requirement of three
`doses per week recited in the claims. Ex. 1004 ¶ 91. In this regard,
`Dr. Green testifies that setting a course of treatment for the same day
`each week, for example on Monday, Wednesday, and Friday, is an
`easier dosing schedule to follow than every other day, which would
`occur on different days of the week throughout the month. Id. ¶ 105.
`In light of the evidence as a whole, we are persuaded that an ordinary
`artisan would have understood the benefits of less frequent injections
`and, therefore, would have had a reason to reduce Pinchasi’s dosing
`regimen to three times per week.
`We are also persuaded by Dr. Green’s testimony and supporting
`evidence that a person of ordinary skill in the art would have had a
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`reasonable expectation of success in administering 40 mg of GA three
`times a week. We credit Dr. Green’s testimony that an ordinary
`artisan would have considered GA to be a “forgiving drug.” Ex. 1085
`¶ 19. Dr. Green testifies that it was a standard instruction for patients
`who miss a dose to skip the dose rather than take a double dose.
`Ex. 1004 ¶ 90 (citing Ex. 1062, which states, “If you miss a dose [of
`GA], take it as soon as you remember. If you do not remember until
`the following day, skip the missed dose and continue with your
`regular dosing schedule.”); Ex. 1085 ¶ 19 (citing Ex. 1086, which
`states, “If you miss a dose, take your COPAXONE® as soon as you
`remember. If it is nearer to the time of your next scheduled dose, skip
`the missed dose and resume your usual dosing schedule.”)13.
` Dr. Green also explains that the wide range of likely
`efficacious doses suggests the forgiving nature of GA. Ex. 1085
`¶¶ 20–21. Flechter and Khan 2008/Caon 2009 disclose 20 mg of GA
`every other day (i.e., 70 mg per week), whereas Pinchasi discloses 40
`mg of GA daily (i.e., 280 mg. per week). Ex. 1008; Ex. 1010;
`Ex. 1011; Ex. 1005, 9:2–11. Because 40 mg three times a week (i.e.,
`120 mg per week) is in the middle of the range of known effective
`weekly doses and is close to the FDA-approved 20 mg daily regimen
`(i.e., 140 mg per week), we are persuaded by Dr. Green’s testimony
`that a person of ordinary skill in the art would have reasonably
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`13 We note that Patent Owner has moved to exclude Ex. 1086. We
`deny Patent Owner’s motion, for the reasons stated in more detail
`below.
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`expected 40 mg of GA three times a week to be successful. Ex. 1085
`¶ 21.
`
`Patent Owner contends that a person of ordinary skill in the art
`would not have found the claimed dosing regimen obvious because
`the mechanism of action of GA was still unknown, which would have
`taught away from three times weekly dosing. PO Resp. 22–28.
`According to Patent Owner and its declarant, Dr. Tjalf Ziemssen,
`based on the prevalent theories on GA’s mechanism of action, an
`ordinary artisan would have believed that administering the drug more
`frequently than once daily would be the best way to enhance efficacy.
`Id. at 25; Ex. 2135 ¶¶ 44– 150. We do not, however, find Dr.
`Ziemssen’s testimony persuasive, given the various prior art
`references that teach less frequent dosing of GA, thereby contradicting
`Dr. Ziemssen’s opinion. See, e.g., Ex. 1005 (Pinchasi dosing every
`other day); Ex. 1008 (Flechter dosing every other day); Ex. 1010
`(Khan 2008 dosing every other day), Ex. 1089 (Khan 2009 dosing
`twice a week). We also credit the testimony of Dr. Green, who
`explains that, given the uncertainty regarding GA’s mechanism of
`action, a person of ordinary skill in the art would not rely on any
`single theory in deciding which dosage regimen to pursue. Ex. 1085
`¶ 44. Dr. Green continues, stating that “[i]f anything, the uncertainty
`surrounding GA’s mechanism of action would motivate a POSA to
`investigate dosing regimens with existing and even preliminary
`clinical support.” Id.
`Patent Owner also argues that a person of ordinary skill in the
`art would not have combined Pinchasi with the 1996 SBOA to arrive
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`at the claimed dosing regimen. PO Resp. 32–35. Patent Owner
`asserts that, although Pinchasi discloses the use of 40 mg of GA, the
`later FORTE results would have caused an ordinary artisan to discard
`the 40 mg dose altogether. Id. at 32. Patent Owner also notes that
`Pinchasi does not suggest dosing three times weekly, and that the
`1996 SBOA does not cure either deficiency of Pinchasi. Id. at 33.
`As explained above, we reject Patent Owner’s argument that
`Pinchasi teaches away from the use of 40 mg of GA. As for the three
`times weekly dosing regimen, Patent Owner asserts that an ordinary
`artisan would have ignored the suggestion for less frequent dosing in
`the 1996 SBOA because the suggestion was based on the erroneous
`belief that GA was acting as a “peptide vaccine.” Id. at 34. We are
`not persuaded, particularly in light of Dr. Green’s testimony that it did
`not matter to an ordinary artisan in 2009 that GA was not a peptide
`vaccine because the ultimate conclusion still holds in light of the prior
`art clinical observations that made it clear that daily injections were
`unnecessary. Ex. 1065, 151:24–155:5. In other words, even if an
`ordinary artisan knew GA was not a peptide vaccine in 2009, the 1996
`SBOA must still be read in the context of the prior art as a whole,
`which suggested less frequent dosing of GA was desirable. See In re
`Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986) (stating prior art
`“must be read, not in isolation, but for what it fairly teaches in
`combination with the prior art as a whole”); see also In re Young, 927
`F.2d 588, 591 (Fed. Cir. 1991) (“[A] reference which disclosed
`obsolete technology remained in the prior art. This court considered
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`the reference for what it disclosed in relation to the claimed
`invention.”).
`Finally, Patent Owner asserts that a person of ordinary skill in
`the art would not have had a reasonable expectation of success that the
`claimed dosing regimen would be effective. PO Resp. 36–50. Patent
`Owner argues that because t